Mechanistic Studies of Transition-Metal-Catalyzed [2 + 2 + 2] Cycloaddition Reactions

Abstract

The development of catalytic methodologies involving the formation of C−C bonds to enable the generation of cyclic systems constitutes a field of great relevance in synthetic organic chemistry. One paradigmatic process to accomplish this goal efficiently is the transition-metal-catalyzed [2 + 2 + 2] cycloaddition reaction, since it permits the formation of a wide range of highly functionalized 6-membered carbo-and heterocyclic molecules in a single step with high efficiency and perfect atom economy. A key feature of these transformations is the mechanistic pathway that they follow, since a deep knowledge of this mechanism may enable us to understand and improve the efficiency of the reaction. This review covers the mechanistic aspects, studied both from theoretical and experimental points of view, of the transition-metal-catalyzed [2 + 2 + 2] cycloaddition reaction involving all kinds of unsaturated substrates with metals such as Co, Ni, Ru, Rh, Ir, Pd, Zr, Ti, Ta, and Nb. A thorough overview is undertaken, from the seminal studies until the present day, of the key mechanistic aspects that influence the reactivity and selectivity of the reaction, comparing the involvement of different unsaturated substrates as well as the different transition metals used.

Practical Synthesis of α‐Trifluoromethylated Pyridines Based on Regioselective Cobalt‐Catalyzed [2+2+2] Cycloaddition using Trifluoromethylated Diynes with Nitriles

“…On the basis of the above results and previous reports, [8d,11a,12] two types of proposed mechanisms for the cobalt‐catalyzed [2+2+2] cycloaddition of the fluoroalkylated diynes 2 with nitriles 1 are depicted in Scheme 4 [13] . Thus, the cobalt(II) catalyst is reduced by Zn/ZnBr 2 system to generate the cobalt(I) active species [14] .…”

Multicomponent syntheses of 5- and 6-membered aromatic heterocycles using group 4–8 transition metal catalysts

“…The multicomponent synthesis of pyridines has been extensively studied, in particular strategies involving the formal [2 + 2 + 2] cycloaddition of alkynes and nitriles. 11,13,22,[69][70][71][72][73][74] This topic has been the subject of numerous recent reviews, so this perspective will focus primarily on comparing and contrasting mechanistic and scope aspects of the group 4-8 catalysts. In the context of group 4-8 metal-catalyzed [2 + 2 + 2] syntheses, methods are primarily dominated by Ru and Fe, although there are several emergent examples with group 4 and 5 that suggest they may have unrealized potential for pyridine synthesis as well.…”

“…Compared to other transition metals, Ru-based catalysts provide complementary access to pyridines with electron-decient nitriles, [80][81][82] which are oen challenging substrates for later transition metals like Co. 83 In contrast, cycloaddition using simple nitriles such as MeCN and PhCN is challenging with Ru due to oen endothermic nitrile insertion, 81 although examples of partially or fully intermolecular [2 + 2 + 2] cycloaddition with nitriles containing coordinating groups have been reported. 81,84,85 Detailed experimental and computational studies (both of [2 + 2 + 2] alkyne cyclotrimerization and pyridine formation) 22,86 have revealed that Cp*RuCl(COD)-catalyzed reactions of a,udiynes likely proceed rst through initial oxidative cyclization of the diyne to form ruthenacyclic biscarbenoid IM32. This intermediate, which related complexes have been structurally characterized via X-ray crystallography and NMR in several instances, 87 is shared between [2 + 2 + 2] pyridine formation, alkyne cyclotrimerization, and [2 + 2 + 1] pyrrole/furan/ thiophene synthesis (vide supra).…”

“…Many such catalytic MCRs have been demonstrated by group 9-11 metals. 13,[22][23][24][25] In recent years, the earlier group 4-8 metals have increasingly emerged as useful catalysts for 5-and 6-membered heterocycle syntheses, and oen have advantages with respect to cost and earth abundance. 26,27 Although groups 4-8 are oen considered quite disparate in their properties, there is strikingly signicant overlap in multicomponent synthetic strategies using these elements, in particular in the synthesis of pyrroles and pyridines (Fig.…”

Theoretical Study of the Mechanism of Palladium(0)‐Catalyzed Intramolecular [2+2+2] Cycloaddition of Ester‐Substituted Alkynes

“…[ 2 ] In addition to these synthetic advantages, the transition‐metal‐catalyzed alkyne [2+2+2] cycloaddition has also attracted considerable attention from a mechanistic point of view. [ 3 ] Based on the isolation of metallacyclopentadiene intermediates, Shore proposed the so‐called “common mechanism”, illustrated in Scheme 1a. [ 4 ] Bis(alkyne) complex A undergoes oxidative coupling (OC) to produce metallacyclopentadiene intermediate B .…”